Polygenic mutations model the pleiotropic disease of Fanconi Anemia

Fanconi Anemia (FA) is a prototypic genetic disease signified by heterogeneous phenotypes including cancer, bone marrow failure, short stature, congenital abnormalities, infertility, sub-mendelian birth rate, genome instability and high cellular sensitivity to cancer therapeutics[1][1]-[4][2]. Clinical diagnosis is confirmed by identifying biallelic, homo- or hemizygous mutations in any one of twenty-three FANC genes[1][1],[5][3]. Puzzlingly, inactivation of one single Fanc gene in mice fails to faithfully model the human disease manifestations[6][4]-[8][5]. We here delineate a preclinical Fanc mouse model with mutations in two genes, Fancd1/Brca2 and Fanco/Rad51c , that recapitulates the severity and heterogeneity of the human disease manifestations including death by cancer at young age. Surprisingly, these grave phenotypes cannot be explained by the sum of phenotypes seen in mice with single gene inactivation, which are unremarkable. In contrast to expectations from classic epistasis analysis of genetic pathways, the data instead reveal an unexpected functional synergism of polygenic Fanc mutations. Importantly in humans, whole exome sequencing uncovers that FANC co-mutation in addition to the identified inactivating FANC gene mutation is a frequent event in FA patients. Collectively, the data establish a concept of polygenic stress as an important contributor to disease manifestations, with implications for molecular diagnostics. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-4 [3]: #ref-5 [4]: #ref-6 [5]: #ref-8